Clinically useful antagonists exist for estrogens, androgens and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. We have tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic- pituitary-adrenal axis, when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. RU 486 potentiated the inflammatory/immune response to a standard stimulus in intact animals, suggesting that glucocorticoids exert antiinflammatory/immunosuppressive effects at physiological levels. We recently demonstrated that corticotropin releasing hormone (CRH) is produced locally at the site of inflammation and has profound pro- inflammatory effects at an autocrine/paracrine level. We have called this "immune" CRH. Glucocorticoids suppress, and RU 486 markedly augments local secretion of immune CRH at an inflammatory site. RU 486 allowed the identification of a central nervous system defect in rats prone to arthritis. In these animals the glucocorticoid response to stress-mediators is inadequate to restrain the immune system following an insult. The actual defect is global and located at the level of the hypothalamic CRH neuron, which responds poorly to all its known stimulants, including several cytokines as well as serotonin, acetylcholine and norepinephrine. This pathophysiologic mechanism is novel and its relevance to human arthritis and autoimmune disease will be examined.